rs121909541

Positions:

• chr14-20693772-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001097577.3(ANG):​c.208A>G​(p.Ile70Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000691 in 1,614,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (0 hom.)
• Consequence: ANG NM_001097577.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:7
• Conservation: PhyloP100: 0.228

Genes affected

ANG (HGNC:483): (angiogenin) The protein encoded by this gene is a member of the RNase A superfamily though it has relatively weak ribonucleolytic activity. This protein is a potent mediator of new blood vessel formation and thus, in addition to the name RNase5, is commonly called angiogenin. This protein induces angiogenesis after binding to actin on the surface of endothelial cells. This protein also accumulates at the nucleolus where it stimulates ribosomal transcription. Under stress conditions this protein translocates to the cytosol where it hydrolyzes cellular tRNAs and influences protein synthesis. A signal peptide is cleaved from the precursor protein to produce a mature protein which contains a nuclear localization signal, a cell binding motif, and a catalytic domain. This protein has been shown to be both neurotrophic and neuroprotective and the mature protein has antimicrobial activity against some bacteria and fungi, including S. pneumoniae and C. albicans. Due to its effect on rRNA production and angiogenesis this gene plays important roles in cell growth and tumor progression. Mutations in this gene are associated with progression of amyotrophic lateral sclerosis (ALS). This gene and the neighboring RNase4 gene share promoters and 5' exons though each gene then splices to a distinct 3' exon containing the complete coding region of each gene. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2020]

RNASE4 (HGNC:10047): (ribonuclease A family member 4) The protein encoded by this gene belongs to the pancreatic ribonuclease family. It plays an important role in mRNA cleavage and has marked specificity towards the 3' side of uridine nucleotides. Alternative splicing results in four transcript variants encoding the same protein. This gene and the gene that encodes angiogenin share promoters and 5' exons. Each gene splices to a unique downstream exon that contains its complete coding region. [provided by RefSeq, Aug 2013]

ENSG00000259171 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12110469).
• BP6: Variant 14-20693772-A-G is Benign according to our data. Variant chr14-20693772-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 18079.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}. Variant chr14-20693772-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000716 (109/152338) while in subpopulation NFE AF= 0.0011 (75/68028). AF 95% confidence interval is 0.000902. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 109 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANG	NM_001097577.3	c.208A>G	p.Ile70Val	missense_variant	2/2	ENST00000397990.5	NP_001091046.1
RNASE4	NM_002937.5	c.-17-5583A>G		intron_variant		ENST00000555835.3	NP_002928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANG	ENST00000397990.5	c.208A>G	p.Ile70Val	missense_variant	2/2	1	NM_001097577.3	ENSP00000381077.4
RNASE4	ENST00000555835.3	c.-17-5583A>G		intron_variant		1	NM_002937.5	ENSP00000452245.1
ENSG00000259171	ENST00000553909.1	c.86+122A>G		intron_variant		2		ENSP00000477037.1

Frequencies

GnomAD3 genomes AF: 0.000716 AC: 109 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000732 AC: 184 AN: 251494 Hom.: 1 AF XY: 0.000817 AC XY: 111 AN XY: 135920

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.000967

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000688 AC: 1006 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.000711 AC XY: 517 AN XY: 727248

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.000724

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000738 AC XY: 55 AN XY: 74506

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00216

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00104 Hom.: 1

Bravo AF: 0.000597

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000610 AC: 74

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	This variant is associated with the following publications: (PMID: 29525178, 23665167, 23047679, 17900154, 18852347, 16501576, 23393617, 18087731, 22190368, 33875291) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Amyotrophic lateral sclerosis type 9 Pathogenic:1 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2008	- -
Uncertain significance, criteria provided, single submitter	research	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University	Mar 31, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 11, 2021

- -

ANG-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	7.9
DANN	Benign	0.51
DEOGEN2	Benign	0.069	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.60	.;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.85	L;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.48	N;N
REVEL	Uncertain	0.59
Sift	Benign	0.26	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.25	B;B
Vest4		0.10
MVP		0.74
MPC		0.19
ClinPred		0.0097	T
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909541; hg19: chr14-21161931; COSMIC: COSV100390994;